1. Field of the Invention
The invention relates to a process for the synthesis of high purity d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime (also known as norelgestromin) comprising acetylation of d-norgestrel at position 17; oximation of the oxo group at position 3 of the obtained d-(17α)-13-ethyl-17-(acetyloxy)-18,19-dinorpregn-4-ene-20-yn-3-one; and then hydrolyzing the acetyloxy group at position 17 of the obtained d-(17α)-13-ethyl-17-(acetyloxy)-18,19-dinorpregn-4-ene-20-yn-3-oxime derivative.
2. Background Art
The investigation of the metabolism of norgestimate is described in Am. J. Obstet Gynecol. 163:2127-31. (1990). The authors disclosed that, after oral administration, the metabolites of d-norgestimate include norelgestromin, d-(17α)-13-ethyl-17-(acetyloxy)-18,19-dinorpregn-4-ene-20-yn-3-one (d-norgestrel acetate), and d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one (d-norgestrel), all of which have some biological activity.
The efficacy and safety of norgestimate/ethinyl estradiol used as a third generation contraceptive are described in Am. J. Obstet. Gynecol. 166:1969-1977. (1992). That same article reports that the main metabolite of norgestimate is norelgestromin, which has a similar pharmacological profile, than norgestimate. After oral administration, norelgestromin is detectable in the blood serum after a short period of time.
U.S. Pat. No. 5,876,746 describes the use of norelgestromin, either alone or in combination with an estrogen component, in a transdermal patch to inhibit fertility.
Hungarian Patent No. 165356 describes the synthesis of dl- as well as d-norgestrel. The starting material of the synthesis is the racemic or the optically active 13-ethyl-3-methoxygona-2,5(10)-diene-17β-ol, which is reacted with hydroxylammonium chloride in pyridine at 100° C. Then the obtained 13-ethyl-3-(hydroxyimino)-gon-4-ene-17β-ol is oxidized at position 17, followed by ethinylation of the oxo group at position 17, to give the dl-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime, or norelgestromin. Although the synthesis of the intermediates, the dl-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime and norelgestromin, are described, the identification and the purity (the quality requirements) as well as the pharmacological activity of these compounds are not provided.
U.S. Pat. No. of 4,027,019 describes the synthesis of the 17-acetoxy and the ester derivatives of norelgestromin in general, as well as the pharmacological activity thereof.